EP0309424A2 - Dérivés amidinyls - Google Patents

Dérivés amidinyls Download PDF

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Publication number
EP0309424A2
EP0309424A2 EP88830376A EP88830376A EP0309424A2 EP 0309424 A2 EP0309424 A2 EP 0309424A2 EP 88830376 A EP88830376 A EP 88830376A EP 88830376 A EP88830376 A EP 88830376A EP 0309424 A2 EP0309424 A2 EP 0309424A2
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Prior art keywords
alkyl
compound
formula
hydroxy
acid
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German (de)
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EP0309424A3 (fr
Inventor
Enzo Cereda
Arturo Donetti
Marco Turconi
Giovanni Battista Schiavi
Rosamaria Micheletti
Antonio Giachetti
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Instituto de Angeli SpA
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Instituto de Angeli SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • the present invention relates to novel pharmacologically active amidino derivatives, to the process for their preparation and to the pharmaceutical compositions containing them.
  • the new compounds are muscarinic receptors blocking agents useful for the treatment of gastrointestinal disorders.
  • muscarinic receptor blocking agents gives rise to a number of pharmacological effects like decreased gastrointestinal motility, inhibition of acid secretion, dry mouth, mydriasis, urinary incontinence, decreased sweating, tachycardia.
  • antimuscarinic agents with tertiary amine structures may give rise to central effects owing to their penetration across blood-brain barrier.
  • the lack of selectivity among these actions makes it difficult to address therapy in one specific indication and this prompted chemical modification of these agents.
  • One of these modifications consists in quaternization of the tertiary amine function to prevent penetration into the brain.
  • the quaternary drugs lack prominent central actions and additionally show a selective greater effect on the gastrointestinal tract, while displaying a minor incidence of side-effects.
  • their major drawback is the poor and unreliable absorption for oral administration unexploitable for therapeutical purpose.
  • amidino derivatives endowed with a strong antimuscarinic activity which show a further enhanced activity on the gastrointestinal tract associated with a lack of central and peripheral effets such as mydriasis, tachycardia and dry mouth.
  • the new amidino derivatives are potentially useful as therapeutically active agents in the management of gastrointestinal motility disorders, such as the spastic condition of the gut, functional diarreha, constipation, irritable bowel syndrome, cardiospasm, pylorospasm, gastro-oesophageal reflux, petic ulcer disease, spasm of the urinary and biliary tracts and urinary incontinence.
  • the compounds (I) are used as such or under the form of tautomers or of physiologically compatible acid addition salts.
  • acid addition salts includes salts with inorganic or organic acids.
  • physiologically compatible acids used for salification include, for example, salts formed with maleic, citric, hydrochloric, tartaric, hydrobromic, fumaric, nitric, sulphuric, methanesulphonic or hydroiodic acid.
  • Some compounds of formula (I), according to the present invention contain one or two asymmetric carbon atoms.
  • the compounds may therefore occur as enantiomers of (+) and (-) type, as diastereoisomers or mixture of them.
  • the present invention includes therefore both the individual isomers and the mixture thereof. It has to be understood, that when mixture of optical isomers are present, they may be separated according to the classic resolution methods based on their different physico-chemical properties, e.g. by fractional crystallization of their acid addition salts with a suitable optically active acid or by the cromatographic separation with a suitable mixture of solvents.
  • lower alkyl means a straight or branched alkyl group having preferably 1 to 5 carbon atoms.
  • aryl preferably means phenyl.
  • cycloalkyl preferably means that the ring has 3 to 7 carbon atoms.
  • a saturated 6-membered heterocyclic ring preferably means piperidine.
  • R 3 and R 4 together with the nitrogen atom to which they are attached form a saturated 5- to 7-membered heterocyclic ring which may contain one or two nitrogen or an endocyclic carboxamido group, it may be pirrolidine, piperazine, homopiperazine,2-oxopiperazine or piperidine which may optionally contain in its inside -CH 2 -CH 2 - or such as desmethyltropane or 6,7-epoxydesmethyltropane.
  • cycloalkyl carboxylic acid preferably means cyclohexane carboxylic acid.
  • arylalkylene prefe rably means diphenylmethylene group.
  • hydroxy Ci- 5 alkyl preferably means hydroxymethyl.
  • unsaturated 6-membered heterocyclic ring preferably means pyridine.
  • the compounds of general formula(l) of the present invention may for example be prepared by the following processes, well known in their general lines to the technicians of the branch.
  • the reaction is conveniently carried out in a polar solvent such as methanol, ethanol, acetonitrile, acetone, ethylacetate or a mixture of them.
  • a polar solvent such as methanol, ethanol, acetonitrile, acetone, ethylacetate or a mixture of them.
  • the reaction temperature is generally kept between 10°C and 70° C, preferably at room temperature.
  • the same compounds may be also obtained by desulphurizing a thiourea of general formula (IV) in which A and R 1 are as above defined,with Raney/Nickel or H 2 0 2 in an appropriate solvent selected from dichloromethane, chloroform, methanol, ethanol, water or a mixture of them.
  • the process is conveniently carried out at a temperature between 10° C and 70° C, preferably at room temperature.
  • the thiourea derivatives of general formula (IV), used as starting material in the above process may be prepared by reacting a compound of formula (II) or its hydrochloric acid addition salt with an isothiocyanate of general formula (V) where R 1 is as hereinbefore defined, or with ammonium thiocyanate.
  • the reaction is carried out in solvents such as water, methanol, ethanol, tetrohydrofurane, acetone,preferably tetrahydrofurane or water, or without solvents, at a temperature ranging from 0°C to 200°C, prefarably at room temperature or at 100°C, or at the melting point of the mixture of the reagents.
  • R 1 in the compounds of general formula (I) is a hydrogen atom
  • the compounds of formula (II) are reacted with a cyano alkyl derivative of formula (VII) in which R is as above defined, in the presence of a Lewis acid such as aluminium chloride, zinc chloride, iron III chloride, tin IV chloride, triphenyltin chloride, preferably aluminium chloride.
  • a Lewis acid such as aluminium chloride, zinc chloride, iron III chloride, tin IV chloride, triphenyltin chloride, preferably aluminium chloride.
  • the reaction is optionally carried out in an inert, high-boiling, halogenated hydrocarbon such as chlorobenzene, tetrachloroethane or without any solvents as a molten mass.
  • the reaction temperature ranges from 50°C to 200° C, preferably at the boiling point of the selected solvent.
  • These compounds may be also prepared by reacting a compound of formula (11) with a reactive compound of formula (VIII) where W is a suitable leaving group selected from 3,5-dimethylpyrazol-1-yl, Ci-5 thioalkyl, preferably thiomethyl, or sulphonyl.
  • W is a suitable leaving group selected from 3,5-dimethylpyrazol-1-yl, Ci-5 thioalkyl, preferably thiomethyl, or sulphonyl.
  • Compounds of formula (VIII) if necessary, may be reacted in the form of their addition salts with mineral or organic acid of formula HX, as hereinbefore defined.
  • the reaction is carried out in polar solvents such as methanol, ethanol, acetonitrile, acetone, water or mixture of them at a temperature ranging from 20°C to 100°C, preferably at the reflux temperature of the selected solvent.
  • nitroguanidine derivative of general formula wherein A and R are as hereinbefore defined,with hydrogen or a hydrogen donor such as formic acid, acetic acid, ammonium formate, cyclohexene, cyclohexadiene, preferably formic acid in the presence of a suitable catalyst, preferably Pd/C or Pd black, in the presence or in the absence of a suitable solvent such as formic acid, water, methanol, ethanol or mixtures of them, preferably formic acid.
  • reducing agents such as titanium III chloride in hydroalcoholic solvents or tin II chloride in diluted formic acid.
  • reaction is performed at a temperature ranging from 10°C to 100°C, preferably at 40°C.
  • Compounds of formula (IX), used as starting material in the above process may be prepared by reacting a compound of formula (II) with a reactive intermediate of general formula (X) wherein W is as hereinbefore defined.
  • the reaction is carried out in solvents such as methanol, chloroform, methylene chloride or mixtures of them, preferably in a 1:1 mixture of methanol and methylene dichloride, at a temperature ranging from 10° C to 80°, preferably at room temperature.
  • R and R 1 When in particular at least one between R and R 1 is different from hydrogen or from an unsubstituted amino group, they may be prepared by reacting a compound of general formula (XI) where A, R 1 , HX, W are as hereinbefore defined, with a primary or secondary alkyl amino derivative.
  • the reaction is carried out in a polar solvent such as methanol, ethanol, acetonitrile, acetone, water or a mixture of them at a temperature ranging from 0°C to 100° C, preferably at 40° C.
  • Compounds of formula (XI), used as starting material in the above process, are conveniently prepared by reacting a thiourea derivative of formula (IV) with a sulphur alkylating agent selected from methyliodide, ethyliodide or dimethyl sulphate in the presence of a solvent selected from methanol, ethanol, acetone, acetonitrile, water or a mixture of them at a temperature between 20°C and 100°C, preferably at the reflux temperature of the selected solvent.
  • a solvent selected from methanol, ethanol, acetone, acetonitrile, water or a mixture of them at a temperature between 20°C and 100°C, preferably at the reflux temperature of the selected solvent.
  • the same compounds may be also prepared by reacting a compound of formula (XII) with a compound of formula (XV) wherein R is as hereinbefore defined, in the presence of a Lewis acid such as aluminium chloride, zinc chloride, iron III chloride, tin IV chloride, triphenyltin chloride, preferably aluminium chloride.
  • a Lewis acid such as aluminium chloride, zinc chloride, iron III chloride, tin IV chloride, triphenyltin chloride, preferably aluminium chloride.
  • the reaction is optionally carried out in an inert, high-boiling, halogenated hydrocarbon such as dichlorobenzene, tetrachloroethane or without any solvent as a molten mass.
  • the reaction temperature ranges from 50° C to 200° C, preferably at the boiling point of the selected solvent.
  • the compounds of general formula (I) prepared according to the processes as above described may optionally be converted with inorganic or organic acids into the corresponding physiologically compatible acid addition salts, for example, by conventional methods such as by reacting the compounds as bases with a solution of the corresponding acid in a suitable solvent.
  • Particularly preferred acids include for example hydrochloric, hydrobromic, sulphuric or methansulphonic acid.
  • a group of the preferred compounds, according to the present invention, for their better activity as muscarinic receptor blocking agents is the one formed by the compounds of general formula (I) wherein R is a hydrogen atom, a C 1-5 alkyl or an unsubstituted amino group, R 1 is a hydrogen atom or a Ci- 5 alkyl and A is a radical selected from noratropine, norscopolamine, N- -[(2-hydroxy-2-cyc)ohexyl-2-phenyl)-ethyl]-piperazine, N-[(2-hydroxy-2-cyclohexyl-2-phenyl)ethyl]-homopiperazine, N-[(2-hydroxy-2,2-diphenyl)-ethyl]-piperazine, benzeneacetic acid a-phenyl- 4-piperidinyl ester, benzeneacetic acid a-cyclohexyl- 4-piperidinyl ester, benzeneacetic acid a
  • the new compounds of formula (I) according to the present invention have interesting pharmacological properties owing to their ability to antagonize the physiological muscarinic effects in warm blooded animals. Therefore the new compounds are commercially viable in the prevention and in the treatment of motility disorders wherein muscarinic receptors are involved, particularly for spastic condidions of the gastrointestinal tract. and irritable bowel syndrome.
  • Guinea pigs (450-55 g, Dunkin Hartley) were sacrificed by cervical dislocation, and a 2 cm piece of terminal ileum was rapidly excised.
  • the tissue was mounted in a 10 ml organ bath containing Tyrode solution of the following composition: (mM) NaCIl 137; KCI 2.68; CaC1 2 1.82; NaHC0 3 5.9; MgC1 2 1; NaH 2 P0 4 0.42; glucose 5.6.
  • Temperature was 37°C, resting tension 800 mg. Contractions were induced by cumulative addition of bethanechol (0.3-30 ⁇ M), each concentration being left in contact until maximal response was observed. Antagonists were added to the bath 60 min before repeating agonist stimulation.
  • K B (dissociation constant) was estimated by linear regression analysis as: where [B] represents the concentration of the antagonist under study.
  • compositions comprising as active ingredient at least one compound of formula (I), as hereinbefore defined, or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.
  • a pharmaceutical carrier or excipient for pharmaceutical administration the compounds of general formula (I) and their physiologically compatible acid addition salts may be incorporated into the conventional pharmaceutical preparations in either solid liquid form.
  • the compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, capsules, tablets, coated tablets, freeze-dried vials, suppositories and oral drops.
  • the active ingredient may be incorporated in excipients or carrier conventionally used in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, gelatine, magnesium stearate, corn starch, aqueous or non-aqueous vehicles, polyvinylpirrolidone, mannitol, semisynthetic glicerides of fatty acids, sorbitol, propylene glycol, citric acid, sodium citrate.
  • excipients or carrier conventionally used in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, gelatine, magnesium stearate, corn starch, aqueous or non-aqueous vehicles, polyvinylpirrolidone, mannitol, semisynthetic glicerides of fatty acids, sorbitol, propylene glycol, citric acid, sodium citrate.
  • compositions are advantageously formulated at dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
  • Each dosage unit may conveniently contain from 5 mg to 500 mg and preferably from 10 mg to 100 mg.
  • N-alkyl-(thiocarbamoyl) derivative By utilizing the suitable N-alkyl-(thiocarbamoyl) derivative and following the above procedure, the following N-alkyl-(iminomethyl) derivatives were prepared:
  • the active ingredient was mixed with the auxiliary products, and the mixture was passed through a screen and mixed homogeneously in a suitable device.
  • the resulting mixture was filled into hard gelatine capsules (200 mg per capsule); each capsule contains 20 mg of active ingredient.
  • Method of preparation the active ingredient and mannitol were dissolved in an appropriate amount of water for injection. The resulting solution was filtered and filled into vials under sterile conditions. The vials were freeze-dried and stopped with a suitable closure.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP19880830376 1987-09-21 1988-09-19 Dérivés amidinyls Withdrawn EP0309424A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT8721977A IT1231238B (it) 1987-09-21 1987-09-21 Derivati ammidinici
IT2197787 1987-09-21

Publications (2)

Publication Number Publication Date
EP0309424A2 true EP0309424A2 (fr) 1989-03-29
EP0309424A3 EP0309424A3 (fr) 1990-10-10

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EP19880830376 Withdrawn EP0309424A3 (fr) 1987-09-21 1988-09-19 Dérivés amidinyls

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EP (1) EP0309424A3 (fr)
JP (1) JPH01131145A (fr)
KR (1) KR890005051A (fr)
AU (1) AU2237988A (fr)
DD (1) DD283996A5 (fr)
DK (1) DK522788A (fr)
FI (1) FI884304A7 (fr)
HU (1) HUT51245A (fr)
IL (1) IL87793A0 (fr)
IT (1) IT1231238B (fr)
NO (1) NO884176L (fr)
PL (1) PL274754A1 (fr)
PT (1) PT88543B (fr)
YU (1) YU176988A (fr)
ZA (1) ZA887003B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0316852A3 (fr) * 1987-11-13 1990-07-25 The Rockefeller University Inhibiteurs du croisement non enzymatique
GB2249093A (en) * 1990-10-23 1992-04-29 Nat Res Dev Piperidine derivatives and their use in pharmaceutical compositions
US5948792A (en) * 1996-08-01 1999-09-07 Banyu Pharmaceutical Co., Ltd. Fluorine-containing 1,4-disubstituted piperidine derivatives
US6017927A (en) * 1994-12-28 2000-01-25 Yamanouchi Pharmaceutical Co., Ltd. Quinuclidine derivatives and medicinal composition thereof
US6846835B2 (en) 2000-07-11 2005-01-25 Banyu Pharmaceutical Co., Ltd. Ester derivatives
WO2009079392A1 (fr) * 2007-12-14 2009-06-25 Theravance, Inc. Composés contenant de l'amidine utiles comme antagonistes du récepteur muscarinique
WO2009035542A3 (fr) * 2007-09-07 2009-11-26 Theravance, Inc. Composés contenant de la guanidine utilisés en tant qu'antagonistes du récepteur muscarinique

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1226389B (it) * 1988-07-12 1991-01-15 Angeli Inst Spa Nuovi derivati ammidinici e guanidinici
TW201303B (fr) * 1990-07-05 1993-03-01 Hoffmann La Roche
US5750540A (en) * 1995-04-28 1998-05-12 Banyu Pharmaceutical Co., Ltd. 1,4-di-substituted piperidine derivatives
ATE205490T1 (de) * 1995-10-13 2001-09-15 Banyu Pharma Co Ltd Substituierte heteroaromatische derivate
AU2793197A (en) * 1996-05-31 1998-01-05 Banyu Pharmaceutical Co., Ltd. 1,4-disubstituted piperidine derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB752331A (en) * 1948-09-30 1956-07-11 Abbott Lab Improvements in or relating to n, n-disubstituted piperazines and process of preparing the same
IL30281A (en) * 1967-07-11 1971-12-29 Chinoin Gyogyszer Es Vegyeszet Amidine history and process for their preparation
US4433152A (en) * 1981-05-25 1984-02-21 Nippon Chemiphar Co., Ltd. Amidinopiperidine derivatives
JPS6081168A (ja) * 1983-10-13 1985-05-09 Asahi Chem Ind Co Ltd アミジン誘導体

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0316852A3 (fr) * 1987-11-13 1990-07-25 The Rockefeller University Inhibiteurs du croisement non enzymatique
GB2249093A (en) * 1990-10-23 1992-04-29 Nat Res Dev Piperidine derivatives and their use in pharmaceutical compositions
WO1992006958A1 (fr) * 1990-10-23 1992-04-30 British Technology Group Ltd Derives de 4-acetoxy-piperidine, procede servant a leur preparation, et leur utilisation comme antagonistes de recepteur m3 de muscarine
US6017927A (en) * 1994-12-28 2000-01-25 Yamanouchi Pharmaceutical Co., Ltd. Quinuclidine derivatives and medicinal composition thereof
US6174896B1 (en) 1994-12-28 2001-01-16 Yamanouchi Pharmaceutical Co., Ltd. Quinuclidine derivatives and medicinal composition thereof
US5948792A (en) * 1996-08-01 1999-09-07 Banyu Pharmaceutical Co., Ltd. Fluorine-containing 1,4-disubstituted piperidine derivatives
US6040449A (en) * 1996-08-01 2000-03-21 Banyu Pharmaceutical Co Ltd Fluorine-containing 1, 4-disubstituted piperidine derivatives
US6846835B2 (en) 2000-07-11 2005-01-25 Banyu Pharmaceutical Co., Ltd. Ester derivatives
EP1302458A4 (fr) * 2000-07-11 2005-10-19 Banyu Pharma Co Ltd Derives d'ester
US7192969B2 (en) 2000-07-11 2007-03-20 Banyu Pharmaceutical Co., Ltd. Ester derivatives
US7504432B2 (en) 2000-07-11 2009-03-17 Banyu Pharmaceutical Co., Ltd. Ester derivatives
WO2009035542A3 (fr) * 2007-09-07 2009-11-26 Theravance, Inc. Composés contenant de la guanidine utilisés en tant qu'antagonistes du récepteur muscarinique
US7960385B2 (en) 2007-09-07 2011-06-14 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8039489B2 (en) 2007-09-07 2011-10-18 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8198304B2 (en) 2007-09-07 2012-06-12 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8338424B2 (en) 2007-09-07 2012-12-25 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
AU2008299993B2 (en) * 2007-09-07 2013-09-05 Theravance Biopharma R&D Ip, Llc Guanidine-containing compounds useful as muscarinic receptor antagonists
CN101796026B (zh) * 2007-09-07 2013-10-23 施万制药 可用作毒蕈碱受体拮抗剂的含胍化合物
US8785633B2 (en) 2007-09-07 2014-07-22 Theravance Biopharma R&D Ip, Llc Guanidine-containing compounds useful as muscarinic receptor antagonists
KR101517574B1 (ko) * 2007-09-07 2015-05-07 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 무스카린 수용체 길항제로서 유용한 구아니딘을 함유하는 화합물
WO2009079392A1 (fr) * 2007-12-14 2009-06-25 Theravance, Inc. Composés contenant de l'amidine utiles comme antagonistes du récepteur muscarinique
US8017617B2 (en) 2007-12-14 2011-09-13 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists
US8242138B2 (en) 2007-12-14 2012-08-14 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists
US8450362B2 (en) 2007-12-14 2013-05-28 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists

Also Published As

Publication number Publication date
JPH01131145A (ja) 1989-05-24
YU176988A (en) 1990-10-31
IT8721977A0 (it) 1987-09-21
DD283996A5 (de) 1990-10-31
DK522788D0 (da) 1988-09-20
PT88543A (pt) 1988-10-01
FI884304A7 (fi) 1989-03-22
HUT51245A (en) 1990-04-28
KR890005051A (ko) 1989-05-11
EP0309424A3 (fr) 1990-10-10
ZA887003B (en) 1990-05-30
PT88543B (pt) 1992-11-30
FI884304A0 (fi) 1988-09-20
AU2237988A (en) 1989-03-23
IT1231238B (it) 1991-11-26
PL274754A1 (en) 1989-06-12
DK522788A (da) 1989-03-22
IL87793A0 (en) 1989-03-31
NO884176L (no) 1989-03-22
NO884176D0 (no) 1988-09-20

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